DESCRIPTION (applicant's abstract): This application proposes to investigate the activation of primary olfactory bulb neurons and neuroblastoma cells by a cytokine, interleukin 12 (IL-12). This will explore a new area of the interaction between the immune system and the CNS. IL-12 acts at the cusp between the innate and the specific immune response development in the periphery, activating natural killer cells and promoting the differentiation of CD4+ Th1 lymphocytes. Preliminary data provide compelling evidence that there is an IL-12 receptor expressed by neurons, both in vitro and in vivo. Additional data are provided which show that IL-12 treatment leads to induction of the IL-12 receptor and nitric oxide synthase type 1 (NOS-1) leading to the development of an antiviral state in neurons both in vitro and in vivo, promoting recovery and survival from VSV encephalitis. The studies included in this application will 1) use cellular and molecular approaches to characterize the IL-12 receptor of neurons, determine the ontogeny of expression, and if IL-1 2R is internalized with ligand binding; 2) examine the signal transduction pathway for similarities and differences with the pathway described in Th1 Lymphocytes; calcium mobilization, and translocation of NF-kB complexes will be explored; 3) analyze genes induced by IL-I2 treatment of neurons by examination of specific candidates. This work will lead to a greater understanding of the complex and intimate interactions between the immune system and the central nervous system.